Diabetic somatic polyneuropathy (DPN) is one of the commonest long-term complications of diabetes and is a main initiating factor for foot ulceration and lower extremity amputation. Current techniques for the quantification of neuropathy either lack sensitivity (quantitative sensory testing), require expert assessment and assess only the fastest conducting myelinated fibers (electrophysiology) or are invasive (skin/nerve biopsy). Our recent work with corneal confocal microscopy (CCM) confirms that it is a rapid, non- invasive in-vivo clinical examination technique which accurately quantifies nerve damage and repair, is comparable to skin biopsy (an accepted gold standard for assessing small fiber damage), and is able to demonstrate early nerve repair after pancreas transplantation. We now propose to establish CCM as a valid surrogate for human DPN through a set of coordinated studies. First, to establish its ability to diagnose and assess progression of neuropathy we will compare CCM with other established tests of neuropathy in a cohort of patients with Impaired Glucose Tolerance (IGT) and diabetic patients with mild neuropathy over a period of 4 years. Additionally to confirm the ability of CCM to measure therapeutic efficacy, we will compare it with other FDA approved standard tests for neuropathy in patients undergoing pancreas transplantation. Finally, we will explore the role of tear nerve growth factor expression in relation to corneal nerve morphology to provide insights into the pathogenesis of corneal and hence somatic nerve fiber damage. PUBLIC HEALTH RELEVANCE: Studies to accurately diagnose, assess progression and quantify repair in diabetic neuropathy have been hampered by the non-availability of a robust, reproducible and non-invasive surrogate marker of nerve damage. We propose to assess the utility of corneal confocal microscopy, a novel non- invasive surrogate of diabetic neuropathy.